1. Grand Rounds Conference Jinghua Chen, MD, PhD University of Louisville Department of Ophthalmology and Visual Sciences April 3, 2015

2. History CC: Progressive decreased central vision OU for one year. HPI: 27 year old white male presented with progressive decrease central vision with spots in front of both eyes for one year. Patient has known macular changes since 2006.

3. Past Medical History POH: Moderate myopia (-3.50 D OU) Known “macular issue” since 2006 PMH: None Allergy: NKDA FH: Mother “night vision issue” Medication: None

4. Exam ODOS ODOS BCVA: 20/2020/20 Pupils: 4  2 4  2 No RAPD OU IOP: 1211 EOM/CVF:Full OU Ant. Seg: Normal OU Color vision: 9/12 11/12

5. IR Photos Grainy perifoveal RPE stippling (hyperplasia/atrophy)

6. OCT Retina Central macular atrophy, RPE foveal thinning with overlying loss of photoreceptors, OD>OS

7. FA FA: Bull’s eye maculopathy with perifoveal patchy ring window defect OU, no leakage

8. Late Phase FA Central hypofluorescence with perifoveal hyperfluorescence fading of window defect

9. Assessment and Plan 27 year old male with known macular changes since 2006 with more eccentric fixation in last year with Bull’s eye maculopathy OU. 27 year old male with known macular changes since 2006 with more eccentric fixation in last year with Bull’s eye maculopathy OU. Differential Diagnosis Differential Diagnosis Cone dystrophy Cone dystrophy Stargardt’s disease Stargardt’s disease Cone-rod dystrophy Cone-rod dystrophy Central areolar choroidal atrophy Central areolar choroidal atrophy Chronic macular hole Chronic macular hole Fenestrated sheen macular dystrophy Fenestrated sheen macular dystrophy Benign concentric annular macular dystrophy Benign concentric annular macular dystrophy Olivopontocerebellar atrophy (OPCA) Olivopontocerebellar atrophy (OPCA) Ceroid lipofuscinosis Ceroid lipofuscinosis Plan: mf ERG, HVF 10-2 Plan: mf ERG, HVF 10-2 BSCS 2014-2015 Book 12, Retina and Vitreous: 236

10. mf ERG mf ERG Extinguished foveal and decreased parafoveal and peripheral responses OU Delayed P1 implicit time involving fovea OU and parafovea and periphery OD

11. mf ERG First Order Traces Cone photoreceptor dysfunction

12. HVF 10-2 OU: central scotoma OD > OS

13. Diagnosis and Management Diagnosis: Progressive cone dystrophy Diagnosis: Progressive cone dystrophy Management: Management: Observation Observation Sunglasses for photophobia Sunglasses for photophobia Macular Dystrophy Support Group (per patient’s request) Macular Dystrophy Support Group (per patient’s request)

14. Photoreceptor Degeneration Cone dystrophy (photophobia, abnormal color vision and diminished central vision) Cone dystrophy (photophobia, abnormal color vision and diminished central vision) Cone-rod dystrophy (early decrease in central visual acuity, photophobia, color vision defects, and nystagmus, with later development of night blindness (nyctalopia). Cone-rod dystrophy (early decrease in central visual acuity, photophobia, color vision defects, and nystagmus, with later development of night blindness (nyctalopia). Rod-cone dystrophy (nyctalopia and progressive peripheral vision loss.) Rod-cone dystrophy (nyctalopia and progressive peripheral vision loss.)

15. Progressive Cone Dystrophy The prevalence of cone-rod dystrophy is approximately 1/40,000 The prevalence of cone-rod dystrophy is approximately 1/40,000 Heterogeneous group of diseases Heterogeneous group of diseases Onset in teenage or later adult years Onset in teenage or later adult years Secondary rod photoreceptor involvement Secondary rod photoreceptor involvement Overlap between progressive cone and cone-rod dystrophy Overlap between progressive cone and cone-rod dystrophy Abnormal photopic ERG, normal rod-isolated ERG Abnormal photopic ERG, normal rod-isolated ERG Hamel CP. Orphanet J Rare Dis. 2007; 2:7. Thiadens AA, Ophthalmology. 2012; 119:819–26

16. Genetics Dominant cone dystrophy Dominant cone dystrophy 6p21.1 is caused by mutations in the GUCA1A gene, which codes for guanylate cyclase activator, a calcium-binding protein in photoreceptor outer segments 6p21.1 is caused by mutations in the GUCA1A gene, which codes for guanylate cyclase activator, a calcium-binding protein in photoreceptor outer segments Mutation in GUCY2D at 17p13.1 Mutation in GUCY2D at 17p13.1 Autosomal recessive cone dystrophy Autosomal recessive cone dystrophy ABCA4 (1p21-p23) gene, which encodes an ATP-binding cassette (ABC) transporter protein expressed by rod and cone disc membrane and is involved in the transport of vitamin A derivatives to RPE. (ABCA4 also have been implicated in Stargardt’s disease, cone-rod dystrophy, and ‘‘retinitis pigmentosa.’’) ABCA4 (1p21-p23) gene, which encodes an ATP-binding cassette (ABC) transporter protein expressed by rod and cone disc membrane and is involved in the transport of vitamin A derivatives to RPE. (ABCA4 also have been implicated in Stargardt’s disease, cone-rod dystrophy, and ‘‘retinitis pigmentosa.’’) X-linked recessive: Tapetal-like sheen, Mizuo-Nakamura phenomenon X-linked recessive: Tapetal-like sheen, Mizuo-Nakamura phenomenon

17. Management Cone photoreceptor transplantation: Adult Nrl ‐ / ‐ mice expressed only cone-specific genes (PNA, s ‐ opsin and cone arrestin) in photoreceptors, and did not express rod ‐ specific genes (Nrl or rhodopsin) Purified these cone photoreceptors from the mouse retina based on the CD73 cell surface antigen. Transplantation of postnatal day 4 cells into wild type mouse retina mediated optimal integration into the outer nuclear layer (ONL) generating morphologically mature photoreceptors. Restoring daylight vision to AMD, cone ‐ rod dystrophies, or late-stage RP Gene therapy RPGRIP1-deficient dog: a large animal model of cone-rod dystrophy. (Mol Ther. 2014 Feb)Mol Ther. Non allele-specific RNAi knockdown of GCAP1 as a general therapeutic strategy to rescue any GCAP1-based dominant cone-rod dystrophy in human patients. (PLoS One. 2013)PLoS One. Suppressing thyroid hormone Signaling Suppressing thyroid hormone Signaling Preserves cone photoreceptors in mouse models of retinal degeneration. Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina.(Proc Natl Acad Sci U S A. 2014 Mar)Proc Natl Acad Sci U S A. Low vision aids Low vision aids http://www.stemcellsportal.com/first-step-towards-treating-cone-photoreceptor-degeneration

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